Identification of an altered matrix signature in kidney aging and disease

Michael J. Randles, Franziska Lausecker, Qingyang Kong, Hani Suleiman, Graeme Reid, Maria Kolatsi-Joannou, Bernard Davenport, Pinyuan Tian, Sara Falcone, Paul Potter, Tom van Agtmael, Jill T. Norman, David A. Long, Martin J. Humphries, Jeffrey H. Miner, Rachel Lennon

Research output: Contribution to journalArticlepeer-review

43 Scopus citations

Abstract

Background Accumulation of extracellular matrix in organs and tissues is a feature of both aging and disease. In the kidney, glomerulosclerosis and tubulointerstitial fibrosis accompany the decline in function, which current therapies cannot address, leading to organ failure. Although histologic and ultrastructural patterns of excess matrix form the basis of human disease classifications, a comprehensive molecular resolution of abnormal matrix is lacking. Methods Using mass spectrometry-based proteomics, we resolved matrix composition over age in mouse models of kidney disease. We compared the changes in mice with a global characterization of human kidneymatrix during aging and to existing kidney disease datasets to identify common molecular features. Results Ultrastructural changes in basement membranes are associated with altered cell adhesion and metabolic processes and with distinct matrix proteomes during aging and kidney disease progression in mice. Within the altered matrix, basement membrane components (laminins, type IV collagen, type XVIII collagen) were reduced and interstitial matrix proteins (collagens I, III, VI, and XV; fibrinogens; and nephronectin) were increased, a pattern also seen in human kidney aging. Indeed, this signature of matrix proteins was consistently modulated across all age and disease comparisons, and the increase in interstitial matrix was also observed in human kidney disease datasets. Conclusions This study provides deep molecular resolution of matrix accumulation in kidney aging and disease, and identifies a common signature of proteins that provides insight into mechanisms of response to kidney injury and repair.

Original languageEnglish
Pages (from-to)1713-1732
Number of pages20
JournalJournal of the American Society of Nephrology
Volume32
Issue number7
DOIs
StatePublished - Jul 2021

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